Novel ester derivatives of phenylpropanolamine

ABSTRACT

VINYLCARBMATE DERIVATIVES OF PHENYLPROPANOLAMINE HAVING ANTITUSSIVE ACTIVITY. METHOD OF PREPARATION COMPRISES REACTING PHENYPROPANOLAMINE WITH THE APPROPRIATE ACETOACETIC ACID ESTER OR AMIDE IN ANY SUITABLE ORGANIC SOLVENT.

United States Patent Office 3,769,317 Patented Oct. 30, 1973 3,769,317 NOVEL ESTER DERIVATIVES OF PHENYLPROPANOLAMINE Henry Cecil Caldwell, Ambler, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa. No Drawing. Filed Feb. 23, 1971, Ser. No. 118,159 Int. Cl. C07c 103/30 US. Cl. 260-471 A 4 Claims ABSTRACT OF THE DISCLOSURE Vinylcarbamate derivatives of phenylpropanolamine having antitussive activity. Method of preparation comprises reacting phenylpropanolamine with the appropriate acetoacetic acid ester or amide in any suitable organic solvent.

This invention relates to new organic compounds having valuable pharmacodynamic properties. More specifically this invention relates to vinylcarbamate derivatives of phenylpropanolamine having the following structural formula:

FORMULA I -CH-OHCH3 H NC=CH III (3H3 wherein: R is a lower alkoxy or a di-loweralkylamino group. The term lower alkoxy and loweralkyl is here and elsewhere employed to designate a chain containing from one to four carbon atoms.

The preferred and most advantageous compounds of this invention are the compounds wherein R is ethoxy, tertiarybutoxy and diethylamino.

The novel compounds of this invention are particularly useful as bronchodilator and antitussive agents. The similarity in therapeutic activity of phenylpropanolamine and the compounds of this invention may be explained by the occurrence of an in vivo hydrolysis of the vinylcarbamates to the phenylpropanolamine after administration. The compounds of this invention are therefore particularly advantageous as antitussives and bronchodilators because the hydrolysis results in a slower onset of action with a delayed time of peak effect.

The novel compounds of this invention as set forth in Formula I are prepared by reacting molar equivalents of phenylpropanolamine and the appropriate ester or amide of acetoacetic acid in an organic solvent according to the following synthetic procedure:

CH-CH-CH:

CHaCOCI-IzCOR H NHz CH-CH 0 The phenylpropanolamine derivatives as represented by Formula I are preferably employed in combination with either a liquid or solid nontoxic pharmaceutical carrier. A wide variety of pharmaceutical forms useful for oral ingestion may be employed. Advantageously the preparation may take the form of tablets, capsules, powders, troches or lozenges. When a solid form is employed the pharmaceutical carrier may be, for example, lactose, magnesium stearate, starch, gums, such as acacia, terra alba, stearic acid, sorbitol, mannitol, ethyl cellulose or gelatin. The amount of solid carrier will vary widely but preferably is from 25 mg. to about 1 gm. If a liquid carrier is used, the preparation can be in the form of a syrup, elixir, liquid suspension, ampule, or soft gelatin capsule.

Similarly the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

The pharmaceutical forms comprising the above novel phenylpropanolamine compounds are administered in dosage units internally, preferably orally. Advantageously equal daily doses are administered to provide a daily dosage regimen which produces antitussive activity. Each dosage unit Will contain the active medicament in an amount of about 10 mg. to about mg. preferably from about 25 mg. to about 50 mg. Advantageously equal doses will be administered 2 to 4 times daily with the daily dosage regimen being about 20 mg. to about 400 mg. preferably from about 50 mg. to about 200 mg.

The following examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation.

EXAMPLE 1 A mixture of 15.1 g. of phenylpropanolamine and 13.0 g. of ethylacetoacetate in 50 ml. of benzene is heated at reflux for about 3 hours until the calculated amount of water is collected. The warm mixture is treated with charcoal and cooled to yield 3-(fl-hydroxy-a-methylphenethyl)aminocrotonic acid, ethyl ester as a white solid having a melting point of 92.5-93.5 C.

EXAMPLE 2 EXAMPLE 3 A mixture of 30.2 g. of phenylpropanolamine and 31.4 g. of N,N-diethyl acetoacetamide in ml. of benzene is heated at reflux for about two hours until 0.2 mole of water is collected. The mixture is decolorized with charcoal and diluted with hexane. The precipitate formed on cooling is N,N-diethyl-3-(fl-hydroxy-a-methylphenethylamino) crotonamide having a melting point of 86-87" C.

EXAMPLE 4 Ingredients: Mg./ capsule 3 (13-hydroxy-ot-methylphenethyl)aminocrotonic acid, t-butyl ester Peanut oil Disperse the peanut oil in the ester and place in a soft gelatin capsule.

One capsule is administered orally four times a day.

EXAMPLE 5 Ingredients:

3 (,B-hydroxy-a-methylphenethyl)aminocrotonic acid, ethyl ester 50 Calcium sulfate dihydrate 100 Sucrose 25 Starch l5 Talc 5 Stearic acid 3 The sucrose, calcium sulfate and ethyl ester are thoroughly mixed and granulated with hot 10% gelatin solu- Mg./tablet EXAMPLE 6 Ingredients: Mg./capsule N,N diethyl 3 (B-hydroxy-a-methylphenethylamino)crotonamide 75 Lactose 125 The ingredients are thoroughly mixed and filled into a hard gelatin capsule.

One capsule is administered three times a day.

What is claimed is:

1. A chemical compound of the formula:

wherein: R is a lower alkoxy group containing from 1 to 4 carbon atoms or a di-loweralkylamino group in which the loweralkyl group contains from 1 to carbon atoms.

2. A chemical compound according to claim 1 in which R is t-butoxy, being the compound S-(B-hydrOXy-amethylphenethyl)aminocrotonic acid, t-butyl ester.

3. A chemical compound according to claim 1 in which R is diethylamino, being the compound N,N-diethyl-3-(flhydroxy-a-methylphenethylamino crotonamide.

4. A chemical compound according to claim 1 in which R is ethoxy, being the compound 3-(B-hydroxy-a-methylphenethyl)aminocrotonic acid, ethyl ester.

LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXT ON, Assistant Examiner US. Cl. X.R.

mg UNITED STATES PATENT OFFICE v CERTIFICATE OF CORRECTION Patent No. 3,152,317 I mm October 30, 1973 Inventofls) Henry Cecil Caldwell It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

(l olunm 4, line 3 reading "the loweralkyl group contains from .1

1 to carbon atoms." shouldread:

"the loi'reralkyl group contains from 1 to 4 carbon atoms.'

Signed and sealed this 14th Gay-of'May 197b,;

Attestz" ..v 4

EDWARD I-LFLETCHEH, JR. 7 C. MARSHALL DANN I At'testing Officer I I Commissioner of Patents 

